The present invention relates to a series of new hypotensive peptides which are of particular value in the treatment of hypertension induced by failures in the renin-angiotensin system, and to their use in such treatment.
There is considerable evidence that reduction of elevated blood pressure reduces the risks of morbidity and mortality. Elevated blood pressure (hypertension) can be caused by a variety of factors and a large number of drugs are available for the treatment of hypertension, the drug of choice being dictated in large measure by the cause of the hypertension. Angiotensin I is a polypeptide formed by the action of renin upon a plasma protein and is converted to angiotensin II by the action of ACE. Angiotensin II causes constriction of the arterioles and can produce hypertension. Hypertension of this type can be reduced by reducing the plasma concentration of angiotensin which, in turn, can be achieved by inhibiting the activity of renin. The number of available drugs having this type of inhibitory activity is very limited.
Certain peptide derivatives having this type of activity are disclosed in Japanese Patent Application Kokai No. 151166/77 and may be represented by the formula R.sup.a CO--X--His--NH--CH(CH.sub.2 R.sup.b)--CHO, in which R.sup.a and R.sup.b represent various organic groups and His represents the L-histidyl group.
Other polypeptides which have been proposed for use as renin inhibitors are the angiotensinogen fragments described by Szelke et al. [Nature, 299, 555 (1982)] and the statine derivatives described by Boger et al. [Nature, 303, 81 (1983)].
Certain hypotensive peptides closely related to the compounds of the present invention are disclosed in copending U.S. patent application Ser. No. 618,127, filed on 7th June 1984 by the present inventors, now U.S. Pat. No. 4,548,926.
We have now discovered a series of peptide derivatives having a very marked ability to inhibit the activity of renin.